Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.

Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis.

Objectives Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that stimulates angiogenesis during tissue ischemia. In vivo electroporation (EP) enhances tissue DNA transfection. We hypothesized that in vivo EP of plasmid DNA encoding a constitutively expressed HIF-1α gene enhances neovascularization compared to intramuscular (IM) injection alone. Methods Left femoral artery ligation was performed in mice assigned to three groups: (1) HIF-EP (n=13); (2) HIF-IM (n=14); and (3) pVAX-EP (n=12). A single dose of HIF-1α or empty plasmid (pVAX) DNA (20 μl of 5 μg/μl each) was injected into the ischemic adductor muscle followed by EP (group 1 & 3). Mice in group 2 received IM injection of HIF-1α plasmid DNA alone. From pre-ligation to days 0, 3, 7, 14, & 21 post ligation, limb perfusion recovery quantified by Laser Doppler Perfusion Imager (LDPI), limb function and limb necrosis were measured. On day 21, the surviving mice (4 – 5 per group) were sacrificed and adductor muscle tissues stained for necrosis using hematoxylin and eosin (H&E); capillary density (anti-CD31 antibodies); and collateral vessels via anti-α-smooth muscle actin (α-SMA) antibodies. Results In vivo EP of HIF-1α DNA significantly improved limb perfusion (HIF-EP: 1.03 ± 0.15 vs. HIF-IM: 0.78 ± 0.064; P < .05, vs. pVAX-EP: 0.41 ± 0.019; P < .001), limb functional recovery (HIF-EP: 3.5 ± 0.58 vs. HIF-IM, 2.4 ± 1.14; p < 0.05, vs. pVAX-EP: 2.4 ± 1.14; P < .001) and limb auto-amputation on day 21 (HIF-EP: 77% ± 12% vs. HIF-IM: 43% ± 14%; P <.05 vs. pVAX-EP: 17% ± 11%; P < .01). Adductor muscle tissue necrosis decreased (HIF-EP: 20.7% ± 1.75% vs. HIF-IM: 44% ± 3.73; P < .001, vs. pVAX-EP: 60.05% ± 2.17%; P < .0001), capillary density increased (HIF-EP: 96.83 ± 5.72 vessels/hpf vs. HIF-IM: 62.87 ± 2.0 vessels/hpf; P < .001, vs. pVAX-EP: 39.37 ± 2.76 vessels/hpf; P < .0001), collateral vessel formation increased (HI-EP: 76.33 ± 1.94 vessels/hpf vs. HIF-IM: 37.5 ± 1.56 vessels/hpf; P < .0001, vs. pVAX-EP: 18.5 ± 1.34 vessels/hpf; P < .00001) and the vessels were larger (HIF-EP: 15,521.67 ± 1,298.16 μm2 vs. HIF-IM: 7,788.87 ± 392.04 μm2; P < .001 vs. pVAX-EP: 4,640.25 ± 614.01 μm2; P < .0001). Conclusions In vivo EP-mediated delivery of HIF-1α plasmid DNA improves neovascularization in a mouse model of limb ischemia and is potentially suitable non-viral, non-invasive intervention to facilitate therapeutic angiogenesis in critical limb ischemia.

Objective There is a paucity of data on how race affects the clinical presentation and short-term outcome among hospitalized patients with SARS-CoV-2, the 2019 coronavirus . Methods Hospitalized patients ≥ 18 years, testing positive for COVID-19 from March 13, 2020 to May 13, 2020 in a United States (U.S.) integrated healthcare system with multiple facilities in two states were evaluated. We documented racial differences in clinical presentation, disposition, and in-hospital outcomes for hospitalized patients with COIVD-19. Multivariable regression analysis was utilized to evaluate independent predictors of outcomes by race. Results During the study period, 3678 patients tested positive for COVID-19, among which 866 were hospitalized (55.4% self-identified as Caucasian, 29.5% as Black, 3.3% as Hispanics, and 4.7% as other racial groups). Hospitalization rates were highest for Black patients (36.6%), followed by other (28.3%), Caucasian patients (24.4%), then Hispanic patients (10.7%) (p < 0.001). Caucasian patients were older, and with more comorbidities. Absolute lymphocyte count was lowest among Caucasian patients. Multivariable regression analysis revealed that compared to Caucasians, there was no significant difference in in-hospital mortality among Black patients (adjusted odds ratio [OR] 0.53; 95% confidence interval [CI] 0.26-1.09; p = 0.08) or other races (adjusted OR 1.62; 95% CI 0.80-3.27; p = 0.18). Black and Hispanic patients were admitted less frequently to the intensive care unit (ICU), and Black patients were less likely to require pressor support or hemodialysis (HD) compared with Caucasians. Conclusions This observational analysis of a large integrated healthcare system early in the pandemic revealed that patients with COVID-19 did exhibit some racial variations in clinical presentation, laboratory data, and requirements for advanced monitoring and cardiopulmonary support, but these nuances did not dramatically alter in-hospital outcomes.

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32–158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49–86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751

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